Psychopharmacology: a comprehensive review



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PSYCHOPHARMACOLOGY:

A COMPREHENSIVE REVIEW

Jassin M. Jouria, MD



Dr. Jassin M. Jouria is a medical doctor, professor of academic medicine, and medical author. He graduated from Ross University School of Medicine and has completed his clinical clerkship training in various teaching hospitals throughout New York, including King’s County Hospital Center and Brookdale Medical Center, among others. Dr. Jouria has passed all USMLE medical board exams, and has served as a test prep tutor and instructor for Kaplan. He has developed several medical courses and curricula for a variety of educational institutions. Dr. Jouria has also served on multiple levels in the academic field including faculty member and Department Chair; and he serves as a Subject Matter Expert for several continuing education organizations covering multiple basic medical sciences. He has also developed several continuing medical education courses covering various topics in clinical medicine. Recently, Dr. Jouria has been contracted by the University of Miami/Jackson Memorial Hospital’s Department of Surgery to develop an e-module training series for trauma patient management, and is currently authoring an academic textbook on Human Anatomy & Physiology.

ABSTRACT

While pharmacotherapy has emerged as the most commonly used psychiatric management, psychiatric education uncovers a salient neglect of clinical psychopharmacology. The educational objective should be the advancement of information in psychopharmacology that is not restricted to useful drugs, or medications that simply work, but rather a goal that represents the unified facets of scientific, clinical and experimental psychiatry. This course offers a comprehensive review of the fundamentals of psychopharmacology as well as valuable concepts that attempt to integrate psychopharmacological topics with clinical psychopathology and psychiatric theory in general. Additionally, it presents practical information on the targeted therapy, benefits, side effects, drug-drug interactions and suggested doses of psychotropic drugs. The four major classes are discussed- antipsychotics, antidepressants, mood stabilizers and antianxiety/sleeping medications, including updated information on the array of new medications and how they differ from traditional drugs. Further information is provided on the use of benzodiazepines, stimulants and sedatives in the management of other mental health disorders. A section on guidelines for communication is also included to help assist the healthcare professional in order to maximize compliance and to support the patient-therapist-psychiatrist relationship.


COURSE LENGTH

20 credit hours or approximately 53,528 words.



OBJECTIVES

At the completion of this course, participants will be able to:



  1. Describe the basic principles of psychopharmacology.

  2. Describe basic brain and nerve anatomy.

  3. Identify the various neurotransmitters present in the central nervous system, and describe their action.

  4. Discuss the epidemiology of mental health disorders in the United States.

  5. Identify the most recent psychotropic drugs and how they differ from the older medications.

  6. Discuss medications in classes based on their mechanism(s) of action.

  7. Discuss the mechanism of action and targeted therapy of antipsychotics.

  8. Differentiate between the subset of antidepressants, based on their mechanism of action.

  9. Identify the mechanism of action and use of benzodiazepines in mental health problems.

  10. Compare and contrast the use of the major groups of anti-anxiety and mood-stabilizing drugs in different types of mental and personality disorders.

  11. Distinguish between the classes of antipsychotics, antidepressants, benzodiazepines, anti-anxiety, and mood-stabilizing medications.

  12. Compare and contrast between the use and management of stimulants vs. sedatives in mental health disorders.

  13. Discuss the processes of absorption, distribution, metabolism and elimination of medical substances in the body.

  14. Describe the desired effect of antipsychotic medications.

  15. Discuss the goals of treating depression with antidepressant medications.

  16. Describe the ways to work collaboratively with people diagnosed with borderline personality disorder, using medication as a tool.
  17. Describe the desired effects from Mood Stabilizers


  18. Explain the major uses of psychostimulant medications.

  19. Discuss interactions and adverse reactions of different classes of psychotropic drugs.

  20. Classify and describe the possible side effects of psychotropic medications and their management in treatment.

  21. Discuss special considerations of psychotropic drugs for special populations (i.e. elderly or pediatric patients).

  22. Identify safety and ethical issues of prescribing psychotropic drugs.

  23. Explain medication treatment algorithms for depressive disorders, anxiety disorders, ADHD, and bipolar spectrum disorders.

  24. Explain the effect of the major classes of controlled and illicit substances on brain and nerve physiology.

  25. Identify how to effectively communicate with patients and other healthcare professionals about medication types, dosage, drug interactions, and side effects.

  26. Discuss how to develop and support the client-therapist-psychiatrist relationship.

  27. Discuss ethical and legal considerations in providing information about medications to clients.

  28. Explain how new information can be applied to existing patient care problems through consultation process with peers.

OUTLINE

  1. Introduction

  1. Definitions

  2. History of Mental Health

  3. Epidemiology



  1. Principles

  1. Basics of Central Nervous System Anatomy

1. Brain

2. Nervous System

3. Neurotransmitters


  1. Basics of Psychopharmacology

1. Overview of mechanism of actions

2. Overview of goals in management

3. Overview of newer vs. older psychotropic medications

  1. Classification of Psychotropic Medications


  1. Antipsychotics

  2. Antidepressants

  3. Anxiolytics and sedatives

  4. Mood stabilizers

  5. Stimulants

  6. Sedatives / Hypnotics

  7. Miscellaneous drugs: complementary, herbal and over the counter



  1. Adverse Effects of Psychotropic Medications

  1. Drug-drug interactions

  2. Side effects

  3. Orthostatic Hypotension

  4. Sexual dysfunction and hyperprolactinemia

  5. Liver/Kidney dysfunction

  6. SIADH

  7. Bone mineral density



  1. Classification of Mental Health Disorders

  1. Psychotic

  2. Personality

  3. Emotional/Behavioral

  4. Mood



  1. Dosage and Delivery

A. Isolated infusion/Intravenous/Oral

B. Dosing schemes/guidelines

C. Therapeutic vs. Toxic


  1. Special Populations

A. Geriatric

B. Pregnancy

C. Pediatric


  1. Limitations and Inadequacies

  1. Cure vs. Control

  2. Toxicity levels

  3. Patient consent

  4. Safety

  5. Ethical Issues

  6. Patient advocacy

1. Medicare

2. Homeless

3. Addictions


  1. Communication

A. Discussing expectations with patients & family

B. Consultation with peers

1. Cognitive Behavioral Therapy

2. Group Counseling

C. Psychological support


  1. Lifestyle Precautions

A. Domestic awareness

B. Work limitations

C. Social interactions


  1. Conclusion


INTRODUCTION

Presently, psychoactive substances and their synthetic derivatives are used for a variety of mental disorders ranging from clinical depression to psychosis.

At the heart of psychopharmacology lie two important things; psychoactive drugs and mental illness as a clinically diagnosed disorder.

DEFINITIONS

Psychopharmacology refers to the study of drugs, pharmakon, that influence the human mental state, psyche, and behavior.

The terms “mental illness”, “mental disorder”, “psychiatric disorder” and “psychiatric illness” are used interchangeably throughout the course. According to the National Alliance on Mental Illness (NAMI), “a mental illness is a medical condition that disrupts a person's thinking, feeling, mood, ability to relate to others and daily functioning. Just as diabetes is a disorder of the pancreas, mental illnesses are medical conditions that often result in a diminished capacity for coping with the ordinary demands of life” (204).

The terms “psychopharmacologic drugs”, “psychopharmacologic medications”, “psychopharmacologic treatment”, “psychopharmacologic therapy”, “psychiatric drugs”, “psychiatric medications”, “psychotropic drugs”, “psychoactive drugs”, “psychoactive medications”, and “psychotropic medications” are used interchangeably throughout the course. They are used to refer to the drugs used to treat mental illness.

Additionally, the terms “psychiatric treatment” and “psychiatric therapy” are used interchangeably throughout the course. They are defined as the overall interventions, clinical and nonclinical, used to ameliorate mental illness.

HISTORY OF MENTAL HEALTH

Past cultures attributed mental disorders and migraines to demonic possessions. Healers used to hammer or drill holes into the skulls with hard instruments solely made for this purpose: to release the demons occupying the sufferer’s mind (1). Others purged this disease with blood-letting (2). These brutal practices lasted for centuries, until Hippocrates challenged the role of supernatural forces in mental illnesses. Instead, he proposed the idea of physiological abnormalities manifesting as psychological disturbances. His idea brought forth a new treatment approach, albeit not the most scientifically sound one – purging (3). Though this approach didn’t help much more than drilling holes into skulls did, purging introduced the practice of ingesting a substance to induce vomiting. The oral administration of substances was an approach that 100 years later would be used again to administer psychoactive drugs.

During the Middle Ages in England and right up to the 19th century, one popular answer to mental illness came in the form of a place, the Royal Bethlem Hospital, now infamously known as Bedlam. These days, the word bedlam, is synonymous with madness. The mental hospital popularized the institutionalization of the mentally ill. A visitation report made in 1403 recorded the presence of mechanical restraints such as manacles, chains, locks and stocks (4). However, while inhumane treatment of the severely mentally ill may have occurred in the premises, little else is known of the actual treatment of the mad in Bethlem during this period (5).

Soon after, propelled by the Industrial Revolution, asylums were constructed everywhere and became an important aspect of managing mental illness. It became the place to be for the “mad men”.

As medicine developed into the 19th century, Sigmund Freud introduced another treatment approach, psychoanalysis, which included hypnosis. It was widely criticized and dismissed, making way for yet another form of treatment, one that dealt with the somatic system (6). This form of treatment was based on the precept that mental pathology is a result of biochemical imbalance in the body. Its goal was to reestablish this balance in order to restore mental health. Somatic treatment included electroconvulsive therapy, psychosurgery, and psychopharmacology.

The field of psychopharmacology is not a new one. Like many aspects of medicine, its roots date back to ancient times. It has been around for as long as humans have started using psychoactive substances from plant and animal sources. Its beginnings can be traced as far back as the times when hunters and gatherers picked up magic mushrooms and cannabis flowers for use during ritual ceremonies. The mind-altering properties of these substances evoke divine revelations that many took to heart. If you think about it, it isn’t a far cry to say that tribal wars have been fought because of mushrooms. Many have paid with their lives when hallucinatory visions commanded a human sacrifice. The survivors soon paid a price too, and so did their future generations. Unbeknownst to them, they have paved the way for mankind’s first endeavor into what the average modern man would call a “drug habit”. Ignorance was bliss, for awhile at least, before psychological dependence kicked in and ruined the “trip”.

Modern psychopharmacology focuses on the drugs that are clinically relevant to modern psychiatry practice. History has taught medical practitioners the one lesson that their predecessors have paid dearly to learn: control. Intensive research and historical data backed by scientific experiments have lead to the isolation of active compounds from their plant and animal sources, successfully identifying the single chemical entity that makes each psychologically active.

As a result, modern psychopharmacology can boast a wealth of benefits that these active compounds offer to its patients and practitioners alike. Perhaps the most important benefit is the semblance of control that synthetic versions of these drugs give to practitioners and patients. The isolation of active compounds set the foundation for its structural elucidation and ultimately, its synthesis in the laboratory. The association between the two is now known as structure-activity relationship (SAR) and was pioneered by Bovet and his colleagues in the 1930s using psychoactive drugs related to antihistamines (7). Synthetic variations of the same active component allowed scientists to experiment with dosages, routes of administration as well as identify therapeutic and side effects. This new knowledge led to tighter restrictions; and, at the same time, the paradoxical freedom and confidence to experiment with its use.

Let’s take the example of Cannabis sativa, a plant commonly known as weed. Weed contains ∆-9-tetrahydrocannabinol (THC), the principal psychoactive component that is responsible for its hallucinogenic properties. These days, cannabis is much more than just a shaman’s drug of choice for evoking the spirits; it has become a popular research molecule in laboratories. There is widespread interest in its use in the treatment of glaucoma, AIDS wasting, neuropathic pain, treatment of spasticity associated with multiple sclerosis, and chemotherapy-induced nausea. Despite this, the U.S. Food and Drug Administration (FDA) has not approved the use of “medical marijuana” in the country, although, it allows and assists in the scientific research of its medical uses. Presently, there are two cannabinoids that received FDA approval, namely Dronabinol and Nabilone. Additionally, the American Marijuana Policy Project released results of clinical trials that show cannabis as a promising treatment for cancer and AIDS patients. Dronabinol is used in anorexia associated with AIDS (8).

Like many scientific fields, there is always plenty of room for improvement. Perhaps centuries from now, medicine will truly only bring the benefits and eliminate the negative facets altogether. But then again, perhaps not; after all, medicine and menace almost always go hand in hand.

In the context of mental health, there is little doubt that psychopharmacology revolutionized psychotherapy in the 1960s. Aside from those with the severe form of the disease who posed a threat to society, psychopharmacological treatments allowed patients to take an active role in their treatment. The drugs allowed them to go home, hold down jobs and be among their peers; essentially function as normal individuals in polite society. No longer did they carry the stigma of their illness, nor were their peers entitled to even know about it. For the first time in history, mental illness became an acceptable entity in social circles, its ugly presence controlled and hidden by psychoactive drugs.

But once again, this medical advancement came with another price, an ill-concealed one this time. It encouraged the deinstitutionalization of the mentally ill in the U.S. that by the 1980s, there were many of them on the streets, homeless and ill-equipped to take care of themselves. Perhaps the greatest mistake here was overestimating the positive effects of psychopharmacological treatment. Patients were treated with drugs instead of locked up in asylums. This was a good thing - to some extent. However, they were still unprepared to handle the demands of being independent and social individuals. Serious repercussions led to the surge of incarceration of the mentally ill during this time. A 1992 survey found that 7.2 percent of the inmate population in the U.S. prisons was “seriously mentally ill” and 25 percent of that population was being detained without charges until the few of the remaining functioning mental hospitals could accommodate them (9).


EPIDEMIOLOGY

Mental illness is an important cause for concern in both adults and adolescents. The condition often co-exists with other chronic diseases that amount to even greater morbidity and mortality rates. According to the World Health Organization, disability due to mental disorders is higher than cancer and heart disease in developed countries, such as the U.S.

Geographically speaking, the number of depressed individuals is greatest in the Southeastern states with 13.7% in Mississippi and West Virginia vs. 4.3% in North Dakota (10).

Depression in Adults

Using continuously gathered data, the two Centers for Disease Control and Prevention (CDC) surveillance systems, NHANES (national estimates) and BRFSS (state estimates), estimate that the occurrence of depression from 2005-2008 (the most current data published) to be 6.8% of the adult population who participated (10).

When it comes to the prevalence of mental disorders among age groups, the aging population living in nursing homes carries the highest number. Beginning 2004, mental illness as a primary diagnosis was found in 18.7% of 65-74 years old residents and 23.5% over the age of 85 years old. This is no surprise since the onsets of dementia and Alzheimer disease occur between those age groups. Specifically, mood disorders and dementia were commonly diagnosed among those 65-74 years old and 75-84 years old, respectively. The older the residents are, the higher is their chance of being diagnosed with dementia. For example, 41% of residents over the age of 85 years old were diagnosed with dementia. As of 2004, approximately 67% of nursing home residents had a diagnosis of a mental illness (10).

Prevalence of mental disorders in adolescents

According to a National Comorbidity Survey-Adolescent (NCS-A) Supplement published in 2010, the most lifetime prevalent mental disorder in the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) text revision was anxiety (31.9%); followed by behavioral disorders (19.1%), mood disorders (14.3%), and substance use disorders (11.4%). The overall prevalence of disorders with severe impairment and/or distress was 22.2% (11.2% with mood disorders; 8.3% with anxiety disorders; 9.6% behavior disorders). The median age of onset for disorder classes was earliest for anxiety (6 years), followed by 11 years for behavior, 13 years for mood, and 15 years for substance use disorders (11).


PRINCIPLES

BASICS OF CENTRAL NERVOUS SYSTEM ANATOMY

Brain

The human nervous system is basically composed of the central nervous system (CNS) and the peripheral nervous system (PNS). The brain and spinal cord comprises the central nervous system while the peripheral nervous system is composed of spinal nerves that branch from the spinal cord and the brain.

The brain is the most complex organ in the human body. It is divided into three main parts:


  1. Cerebrum

  2. Cerebellum

  3. Brain stem

Cerebrum

The cerebrum is part of the forebrain, along with thalamus and hypothalamus. It is the largest component of the human brain and is further divided into the right and left hemispheres, which are joined together by a collection of white matter of fibers, termed as corpus callosum.

Each of the cerebral hemispheres in the cerebral cortex is further divided into four lobes: the frontal lobe, the parietal lobe, the temporal lobe and the occipital lobe. One of the brain’s most prominent fissures, the lateral sulcus, partitions the frontal and parietal lobes from the temporal lobe above. Similarly, the central fissure called the central sulcus, partitions the frontal lobe above from the parietal lobe below.

An embryonic telencephalon is the equivalent of the cerebral cortex and basal ganglia in the fully developed human brain. The limbic system is a network of structures from the telencephalon, diencephalon and mesencephalon.

Forebrain

The cerebral cortex is the outermost layer of the cerebrum, which is composed of gray matter. The gray matter is made up of neuronal cell bodies, unmyelinated axons, and dendrites, which are important nerve structures involved in communicating muscle movements and sensory perception. The cortex has a folded structure called gyrus accompanied by prominent fissures called sulcus.

Below the cortex are cortical fibers that form a connection with the neurons. Axons are covered by myelin sheath that facilitates the fast conduction of nerve impulses. Myelin is what gives the name of white matter to the cortex. The cortical and the subcortical parts together form the limbic system, which is responsible for the formation of memory and emotional responses. A study by Jong H. Hoon of the University of California-Davis in 2013 suggests that the circuit connecting the prefrontal cortex with the basal ganglia is a site of communication disturbance in schizophrenics. The results of the fMRI data found that schizophrenics have a reduced and increased activities in the prefrontal cortex and the basal ganglia, respectively (191).

The limbic system allows the interaction between the cortex, thalamus, hypothalamus, and the brainstem. It borders the thalamus at both sides, just under the cerebrum, and encompasses the structures hippocampus, amygdala, hypothalamus, and thalamus.

Hippocampus

The hippocampus is made up of two horn-like structures that originate from the amygdala.  It is responsible for making and storing new memories, or short-term memories, into long-term memories. When damaged, the person might recall old memories but unable to make and store new ones. Skills that were learned prior to the damage will still be intact. According to the National Institute of Health (NIH), it may play a role in mood disorders through its control of a major mood circuit called the hypothalamic-pituitary-adrenal (HPA) axis (12).

A study using mouse models, by Schobel et al. published in 2013, found reduced hippocampal size as a result of glutamate-driven hypermetabolism. The results suggest that the brains of patients with schizophrenia may also exhibit significant atrophy of the hippocampus and hypermetabolic activity (192).

Amygdala


Amygdala is made up of two lumps of neurons that are shaped like almonds. When stimulated, the person responds with anger and fear. The so-called fight and flight response is believed to originate from this region. It is also responsible for storing memories that stimulated past fear responses such as falling from a first story window as a child. A full understanding of this structure may be useful in the treatment of phobias, anxiety, and post-traumatic stress disorder (PTSD).

Hypothalamus

The hypothalamus is the thermostat of the body, located in the brain. Its primary function is homeostasis. It is part of the autonomic nervous system that regulates blood pressure, anger, sexual response, heart rate, digestion, anger, etc. The hypothalamic nuclei are positioned on the walls of the third ventricle.

Thalamus


Thalamus is largely made up of gray matter and plays an important role in receiving and filtering all sensory information (except olfactory). A Swedish study published in 2010 found that mentally ill patients, such as schizophrenics, share a common brain feature involving the thalamus with creative individuals. These individuals had lesser dopamine receptors (D2) in their thalamus, which indicates less filtration of information (13).

Under the limbic system is the brain stem. It is made up of the medulla, pons and the midbrain. Each structure is discussed below.

Medulla

The medulla, also called the medulla oblongata, is situated in the lowest part of the brain. It is connected to the midbrain via the pons and continues posteriorly to the spinal cord. The medulla has both gray and white matter in its structure just like the cerebellum and cerebrum. Its primary function is regulation of breathing and heart rate.


Pons

The pons lies superior to the medulla. It has a ventral surface, which is characterized by a band of horizontal fibers that enters the area of contralateral middle cerebellar peduncle and finally the cerebellum. It plays a role in sensory analysis and movement. Its connection to the cerebellum also makes it an important organ in maintaining posture.

Midbrain

The midbrain is the most superior aspect of the brainstem, which lies between the forebrain and hindbrain. It contains a reticular formation, a part of the tagamentum, which is implicated in the regulation of motor functions. On the ventral side of the midbrain, there are two bundles that diverge to form cerebral peduncles. The third cranial nerve (oculomotor nerve) can be seen between the cerebral peduncles. On the posterior side of the midbrain, there are two pairs of protrusions, which are the superior and inferior colliculi.

Cranial nerves

There are 12 pairs of the cranial nerves whose function is to send the motor signals to and from the head and neck.

Cerebellum

The cerebellum occupies the portion of posterior fossa, which is located dorsally to the pons and medulla. It is involved in motor control, posture and balance. The cerebellum encompasses structures like finer folia and fissures similar to gyri and sulci in the cerebrum.

The cerebellum is composed of two hemispheres that are connected at the center by the midline structure, vermis. The cerebellar cortex is made up of three layers: molecular, Purkinje, and granular. Also, there are four deep cerebral nuclei in the cerebellum termed as the fastigial, globose, emboliform, and dentate nuclei.

Aside from these three structural layers, there are also other structures in the brain such as the meninges and cerebrospinal fluid that help it fulfill its overall functions. They are discussed individually, in brief below.

Meninges

There are three layers of meninges that cover the brain and the spinal cord. These are (14):


  • Pia matter

  • Arachanoid layer

  • The dura matter

The innermost of the layers is called the pia meter, which tightly encloses the brain. It is rich in blood vessels. The arachanoid layer is situated outside the pia matter and looks like a thin layer of web. Between these two layers is the arachnoid space, which contains the cerebrospinal fluid.

Cerebrospinal fluid

The brain is completely immersed in a serum-like liquid called the cerebrospinal fluid. It is produced in the choroid plexus and freely circulates around the ventricles of the brain, spinal cord and the subarachnoid space. It is both a mechanical and an immunological barrier that helps keep the brain infection-free and void of mechanical injuries (14, 15).

Nervous System

There are basically two types of cells in the nervous system; the glial cells and the neurons or nerve cells. Glial cells play a supportive role in the synaptic and electrical interactions i.e. they support the nerve cells that are primarily responsible for this role (16).

The main functions of glial cells are to:


  1. Nourish neurons

  2. Provide a structural support to the neurons

  3. Help in the removal of waste products from the neurons

  4. Insulate neurons

Neurons, on the other hand, play a significant role in electrical signaling and synaptic communication in the nervous system and are regarded as the primary line of communication between its various parts.

The neuron is the messenger in the body that receives and processes information before relaying the same information to the brain and other parts of the body. It is made up of three parts; the dendrites, soma and the axons.

Dendrites

Dendrites are the branched extensions from a nerve cell body (soma). They are found in more numbers than axons. Anatomically, they look like numerous twigs and branches that project from a tree. These projections increase the surface area of the cell body. Its primary function is to receive nerve signals from other neurons through its terminals called synapse. Basically, dendrites form the postsynaptic terminal of a synapse.

Soma

Soma is the nerve cell body. It is the most important part of the neuron as it contains the nucleus and other important cellular organelles such as the mitochondria and Golgi apparatus. The presence of these organelles makes the soma the metabolic center of the neuron.



The soma is the part where the signals from the dendrites are received before being passed on further. The cell body and its nucleus maintain the functional role of the overall neuron structure. At the end of the soma is a structure called axon hillock, which controls the firing of the neuron.

Axon


Axons are the single long fibers that extend from the soma. Their primary function is to send information to the muscles, other neurons, the brain and parts of the body. The larger the surface of the axons, the faster is the rate of neuronal transmission between neurons.

At the one end of the axon is the axon terminal, which transmits information across the synapse and into another neuron. The junction between the axon of one neuron and the dendrites of the neighboring neuron is called the synapse (17). The neuron whose axon sends out the information is called the presynaptic neuron and the neuron whose dendrites receive the same information is called the postsynaptic neuron.

A fatty substance coats and insulates the axons called the myelin sheath. The Schwann cells manufacture it, and one of its primary functions is to facilitate and speed up neuronal transmission along the axon fiber.

The resting potential

A fluid found intracellularly and extracellularly of a nerve cell serves as a medium to conduct electrochemical signal in and out of cells. It contains positively and negatively charged molecules (ions), though not in equal concentrations. The membrane that separates the two is called the semi-permeable membrane.

The intracellular compartment harbors more negatively charged ions when at rest, making it a slightly more negatively charged environment. At this state, there are more sodium ions (Na+) outside the neuron than inside it and more potassium ions (K+) inside than outside it. A nucleus at its resting potential is inactive, a state wherein there is a charge of about - 70 mV.

The action potential

When a neuron is stimulated with an electrochemical impulse, its resting potential moves towards 0 mV. It is triggered by the opening of the voltage-gated channels of the neuronal membrane, allowing the inward movement of the sodium ions and increasing the amount of positively charged ions in the neuron. An increased amount of positive charges in the neuron results in its depolarization. When this happens, the channels close and inhibit further inward movement of ions. This short period of time results in a dormant span of about 1-2 milliseconds and is called the absolute refractory period. The neural impulses always follow the All or None Law, which means that neurons only fire an impulse when stimulation reaches a certain threshold. Otherwise, no neural firing happens because a weak stimulus is not strong enough to generate an action potential.

There are certain drugs and poisons that alter the axon conduction. One such example is the antiepileptic drug, levetiracetam. Its exact mechanism is unknown; however it is believed that it inhibits the opening of voltage-gated channels, thereby, blocking the impulse conduction across the synapses.

Similarly, valproic acid, which is another anticonvulsant drug, is used to enhance the transmission of the neurotransmitter GABA by inhibiting GABA transaminase, the enzyme responsible for the breakdown of GABA. The drug also blocks the voltage-gated sodium channels.

Several deadly toxins work similarly; they interfere with neural transmission. As mentioned above, the flow of sodium ions in and out of neurons is a vital step in the conduction of the nerve impulse along the axons. The toxin produced by puffer fish, tetrodotoxin, specifically binds tightly with the sodium ion channels of neural cell membranes and prevent the conduction of nerve impulses along its nerve fibers. The result is respiratory paralysis (18).

Alcohol is another example. It inhibits axonal transmission by blocking the excitatory channels on the postsynaptic neuron. Moreover, it lowers the rate of action potential coming from the presynaptic neuron.

Synapse

An understanding of synaptic transmission is important in understanding the basic principle of chemical signaling between neurons. The biochemical interaction between neurons occurs at the end of the axon, in a structure called synapse.


As briefly mentioned above, a synapse is the gap that forms at the junction between the axon of one neuron and the dendrite of another neuron. It is basically the site, though not a physical one, where an axon terminal ends near a receiving dendrite. As neurons form a network, they need to be interconnected for the purpose of transmission of nerve impulse from one neuron to the other but unlike other cells; there is a lack of a cellular continuity between two neurons, a gap between them called synaptic space. Moreover, these synaptic connections are not inert. Neurons form new synapses or fortify existing synaptic connections in response to new experiences. The constant activity in neuronal connections is the foundation of learning (19).

The mechanism of chemical signaling involves the release of a chemical called neurotransmitter from the presynaptic neuron, which binds with receptors at the postsynaptic neuron to generate an impulse that travels across to the axon terminal to elicit a response.


Neurotransmitters

Neurotransmitters are endogenous chemicals in the human body that are responsible for the transmission of nerve impulses between neurons and target cells across a synapse. Each neuron has a specialized function i.e. whether it is a cholinergic, dopaminergic, and glutamatergic. A dopaminergic neuron primarily synthesizes the neurotransmitter dopamine and a glutamatergic neuron synthesizes the amino acid neurotransmitter, glutamate.

For a signal to get transmitted across, an optimum amount of neurotransmitters in the synaptic space must be present. In mentally healthy individuals, there is a balance between the amount of neurotransmitters in the synaptic space and in the presynaptic neuron. It is the disruption of this balance that leads to mental and metabolic disorders affecting sleep, mood, weight, etc.

Neurotransmitters can be categorized according to their chemical composition, namely:



  1. Small molecule neurotransmitters

  2. Neuropeptide or peptide transmitters

Small molecule neurotransmitters are synthesized at the terminal site of the axon. The enzymes needed for the synthesis of these neurotransmitters are synthesized within the cell body of the neuron and then transported to the nerve terminal cytoplasm by means of a process called slow axonal transport. These enzymes then generate a pool of neurotransmitters in the cytoplasm (20).

The mechanism involved in the synthesis of neuropeptides is different from that of the small molecule neurotransmitters. It involves protein synthesis. The first step involves gene transcription within the nucleus of the cell; a process involving the construction of the corresponding strand of messenger RNA by using a peptide coding sequence of DNA as a template. The messenger RNA then acts as a code to form a sequence of the amino acids, forming the neuropeptide needed at the nerve terminal. (20)

After synthesis, the neurotransmitters, both small molecules and neuropeptides, are stored in small vesicles within the axon terminal, awaiting an action potential to arrive and stimulate their release.

Some of the important neurotransmitters implicated in psychopharmacology are acetylcholine, serotonin, dopamine, norepinephrine, epinephrine, glutamate and GABA. Each one is discussed individually briefly below.

Acetylcholine

Acetylcholine is basically synthesized by the combination of two compounds; choline and acetyl-CoA. The reaction is catalyzed by the enzyme choline acetyltransferase. After its synthesis, it is stored in the vesicles to prevent its degradation by the enzyme, acetylcholinesterase. Acetylcholine is released from its vesicles as a response to an action potential that moves along the motor neuron and carries the depolarization wave to the terminal buttons.

Acetylcholine is used to regulate muscle movement. Its cholinergic neurons are found all over the CNS, especially the brain, where it is involved in numerous functions such as pain perception, neuroendocrine regulation, REM regulation and memory and learning formation. Damage to the cholinergic system is an important pathology implicated in Alzheimer’s disease.

The two main receptors upon which acetylcholine act on are muscuranic and nicotinic receptors. When bound to the ligand-gated ion channels, nicotinic receptors, acetylcholine stimulates the influx of sodium ions, resulting in the depolarization of the effector cells. The succeeding hyperpolarization and slow depolarization are mediated by the binding of acetylcholine with muscarinic receptors, specifically the M2 and M1. All muscuranic receptors are G-protein coupled receptors, which are classified as M1, M2, M3, M4, and M5.

Norepinephrine

Norepinephrine is the neurotransmitter that plays an important role in conditions related to stress. Along with epinephrine, it enables the body to “fight or flight” in emergencies by stimulating the heart rate, blood circulation and respiration to compensate for the increased oxygen requirement of the muscles.

Norepinephrine is the primary neurotransmitter for postganglionic sympathetic adrenergic nerves. It is synthesized within the nerve axon, stored in vesicles and released when an action potential travels downward in a nerve.

It is synthesized from another neurotransmitter, dopamine. The 1st step in its synthesis involves the transport of the amino acid, tyrosine, into the sympathetic nerve axon where tyrosine is converted to DOPA by the enzyme tyrosine hydroxylase. DOPA then gets converted to dopamine, which in turn, is converted into norepinephrine by the enzyme, dopamine beta hydroxylase. Norepinephrine is primarily released into the extracellular space whenever there is an increased intracellular calcium level. Other factors that trigger its release are cyclic nucleotides, phosphodiesterase inhibitors, beta-adrenoceptor agonists, cholinergic nicotinic agonists, and angiotensin.

Norepinephrine is metabolized by the enzyme catechol-o-methyltransferase (COMT) and its final metabolic product is vanillylmandelic acid (21). The norepinephrine transporter (NET) is responsible for the reuptake of extracellular norepinephrine. NET is a target of many antidepressant drugs. A decreased number of NET is associated with Attention Deficit Hyperactivity Disorder (ADHD).

Dopamine


As mentioned just above, dopamine is synthesized from the amino acid, tyrosine. Tyrosine is converted to dopamine by the action of enzymes, tyrosine hydroxylase and L-amino acid decarboxylase, respectively. Just like the other neurotransmitters mentioned previously, dopamine is stored in the vesicles of the dopaminergic neurons. Like norepinephrine, the exocytosis of dopamine is triggered by an increased influx of calcium ions within the neuron.

Two types of transporters called the dopamine transporter (DAT) and vesicular monoamine transporter (VMAT) are implicated in dopamine reuptake. DAT functions as a means of transport for dopamine from the extracellular space to the intracellular space while VMAT is responsible for reloading dopamine back into the vesicles.

Dopamine reuptake inhibitors help to maintain high levels of dopamine at the postsynaptic space, sustaining and prolonging its effects. The main enzymes involved in its metabolism are MAO and COMT (22). The latter is the target enzyme of older antidepressants such tranylcypromine. Deficiency of dopamine in the brain is implicated in the pathology of Parkinson’s disease.

Serotonin

The synthesis of serotonin involves the conversion of another amino acid, L-tryptophan, to 5-hydroxytryptophan, by the enzyme L-tryptophan hydroxylase. The final step involves the decarboxylation of 5-hydroxytryptophan by the enzyme L-aromatic amino acid decarboxylase. Serotonin is metabolized by the enzyme monoamine oxidase inhibitor (MAO) to 5-hydroxyindoleacetic acid (5-HIAA).

The main function of serotonin is regulation of mood, appetite, sleep, cognition, and blood coagulation. The most widely prescribed and efficacious antidepressants, selective serotonin reuptake inhibitors (SSRIs), and older antidepressants such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), act on the serotonergic system by inhibiting serotonin reuptake into the presynaptic vesicle.

Glutamate

Glutamate is the primary excitatory neurotransmitter in the brain. An injury to a nerve (e.g. brain injury) results in its release and excessive concentration in the extracellular space, leading to excitotoxicity. Unlike the other neurotransmitters, it is an amino acid itself, rather than synthesized from it. Its precursor is glutamine (23).

A study conducted by researchers at Columbia University Medical Center (CUMC) and published in the April 2013 issue of Neuron, found that excessive glutamate levels in the brain is a precursor to psychosis in individuals at high risk for developing schizophrenia. The study suggests using its findings as an early diagnostic tool to identify those individuals and consequently correct the increased glutamate levels in order to slow the progression to full blown schizophrenia later in life (192).

GABA


The inhibitory neurotransmitter GABA is synthesized from the amino acid, glutamate, by the enzyme glutamate decarboxylase in the GABAergic neurons. The neurotransmitters are then transported into the vesicles with the help of vesicular transporters. Upon release, these neurotransmitters are taken up with the help of the membrane transporters into the neurons where they can be recycled and metabolized by their respective enzymes (24).




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